Decline in cognitive function is a common occurrence in the aging population. Cognitive impairment has a negative impact on daily activities and quality of life. (Mattson MP et al; Physiol Rev Vol. 82, 2000, pp 637-672). The loss of cognitive function is pronounced and severe in patients suffering from pathological conditions such as Alzheimer's disease or other types of dementia. Further, prominent cognitive deficits are also present in depressed and schizophrenic patients (Blaney PH; Psychol Bull Vol 99, 1986, pp 229-246. Frith C; BR Med Bull, Vol 52, 1996, pp 618-626). Cognitive impairment has a significant impact on the quality of life of these patients. Hence, it is of critical importance that strategies and therapeutics to counteract cognitive decline are developed.
Phosphodiesterases have recently gained increased attention as potential new targets for cognition enhancement. Phosphodiesterases are enzymes that hydrolyze cyclic AMP (cAMP) and/or cyclic GMP (cGMP) in various cell types, including the brain. Evidence is accumulating that second messenger molecules, cGMP and cAMP, are important in memory processes in general and long-term potentiation in particular.
Prickaerts et al (Psychopharmacology Vol 202, 2009, pp 419-443) review the effects of different classes of selective phosphodiesterase inhibitors (inter alia phosphodiesterase 4 inhibitors) in in vivo murine models on cognition enhancement. International patent application WO01/87281 describes the use of a group of phosphodiesterase 4 inhibitors for enhancing cognitive function. Further, Bruno et al (Br J Pharmacol, Vol 164, 2011, pp 2054-2063) describe the effects of GEBR-7b, a PDE4D selective inhibitor, on the object recognition test on rats and mice. Additional studies have shown the effects of L-454,560 a selective phosphodiesterase 4 inhibitor, on the rat water maze Delayed Matching To Position (DMTP) test indicating possible cognitive (i.e., memory) enhancement effects of the compound (Huang Z et al, Biochem Pharmacol Vol 73, 2007, pp 1971-1981). Selective phosphodiesterase 4 inhibitor MK-0952 was tested in rats and showed an improvement of novel object recognition as well as in the Water Maze DMTP test in rats (Gallant M et al, Bioorganic and Medicinal Chemistry Letters 2010, Vol 20 (Issue 22), pp. 6387-6393).
Phosphodiesterase 4 inhibitors (PDE4 inhibitors) are known to produce dose-limiting adverse events, including emesis, nausea and colitis, rendering their clinical development challenging. Therefore, despite efforts through research to overcome these challenges and further due to the narrow therapeutic window of this class of phosphodiesterase 4 inhibitors, none of the tested phosphodiesterase 4 inhibitors has thus far shown (a) a sufficient efficacy in the clinic and at the same time also (b) an acceptable adverse event profile.
It is an object of the present invention to overcome this problem by using a known phosphodiesterase 4 inhibitor in a particular low dose for the treatment of cognitive impairment.
Definitions
As used herein, the term “treating cognitive impairment” or “treatment of cognitive impairment” refer to one or more of the following:                (1) inhibiting the disease and its progression; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or sympathology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) such as in case of cognitive impairment, arresting or delaying a) the decline in memory (long term and/or short term), b) the decline in decision making, c) the decline in executive functions (e.g., reasoning, problem-solving, planning), d) the decline in language skills (e.g., naming, fluency, expressive speech, and comprehension), e) the decline in visuospatial skills, and f) the decline in attentional control (e.g., simple and divided attention),        (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology) such as in case of cognitive impairment, a) improvement in memory (long term and/or short term), b) improvement in decision making, c) improvement in executive functions (e.g., reasoning, problem-solving, planning), d) improvement in language skills (e.g., naming, fluency, expressive speech, and comprehension), e) improvement in visuospatial skills, and f) improvement in attentional control (e.g., simple and divided attention).        
As used herein, the term “mammal” has its ordinary meaning in the art and includes, e.g. humans, mice, rats, rabbits, dogs, cats, bovines, horses, swine and monkey, with preference given to humans.
As used herein, the phrase “cognitive impairment” refers to any decline in one or more of memory functions, decision making, executive functions, language skills, visuospatial skills, or attentional control.
Cognitive impairment may be associated with aging as well as with a variety of disorders. Disorders, which may be mentioned in this connection are, for example, Mild Cognitive Impairment (MCI) associated with Alzheimer's disease, cognitive impairment associated with Alzheimer's disease, cognitive impairment associated with Schizophrenia (CIAS), cognitive impairment associated with Vascular disease, cognitive impairment associated with Parkinson's disease, cognitive impairment associated with Huntington's disease, cognitive impairment due to stroke, cognitive impairment due to attention deficit disorder, cognitive impairment due to depression, frontotemporal dementia due to motor neuron disease and post-operative cognitive decline (POCD) in the elderly.
Sharp demarcations between normal cognition and mild cognitive impairment and between mild cognitive impairment and cognitive impairment associated with Alzheimer's Disease are difficult. Clinical judgment must be used to make these distinctions. As used herein, the phrase “mild cognitive impairment” refers to the symptomatic predementia phase of Alzheimer's disease. Criteria that should be met in order to diagnose a person with “mild cognitive impairment” include the following (Albert M S et al; Alzheimer's & Dementia 2011 Vol 7, pp 270-279):                there should be evidence of concern about a change in cognition, in comparison with the person's previous level        there should be evidence of lower performance in one or more cognitive domains that is greater than expected for the patient's age, and educational background; this lower performance can occur in a variety of cognitive domains, including memory, executive function, attention, language, and visuospatial skills        Persons with mild cognitive impairment commonly have mild problems performing complex functional tasks which they used to perform previously, such as paying bills, preparing a meal, or shopping; they may take more time, be less efficient, and make more errors at performing such activities than in the past        The cognitive changes are sufficiently mild that there is no evidence of a significant impairment in social or occupational life        Scores on cognitive tests for individuals with mild cognitive impairment are typically 1 to 1.5 standard deviations below the mean for their age and education matched peers on culturally appropriate normative data (i.e., for the impaired domain(s)); age and educational norms are available for some tests, as for example Verbal Learning Tests such as California Verbal Learning Test (CVLT) or Fre and Cued Selective Reminding Test (FCSRT).        
In general, “pharmaceutically acceptable salts” refers to salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
Examples of salts with inorganic bases may include salts with alkali metals such as sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc., and salts with aluminum etc.
Examples of salts with organic bases may include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.
Examples of salts with inorganic acids may include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
Examples of salts with organic acids may include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
Examples of salts with basic amino acids may include salts with arginine, lysine, ornithine, etc.; examples of salts with acidic amino acids may include salts with aspartic acid, glutamic acid, etc.
“Unit dosage forms”, as used herein, refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.